Crocin ameliorates neuroinflammation and cognitive impairment in mice with Alzheimer's disease by activating PI3K/AKT pathway.

BACKGROUND: Crocin has a good prospect in the treatment of Alzheimer's disease (AD), but the mechanisms underlying its neuroprotective effects remain elusive. This study aimed to investigate the neuroprotective effects of Crocin and its underlying mechanisms in AD. METHODS: AD mice were set up by injecting Aß25-35 solution into the hippocampus. Then, the AD mice were injected intraperitoneally with 40 mg/kg/day of Crocin for 14 days. Following the completion of Crocin treatment, an open-field test, Y-maze test and Morris water maze test were conducted to evaluate the impact of Crocin on spatial learning and memory deficiency in mice. The effects of Crocin on hippocampal neuron injury, proinflammatory cytokine expressions (IL-1ß, IL-6, and TNF-α), and PI3K/AKT signaling-related protein expressions were measured using hematoxylin and eosin staining, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) experiments, respectively. RESULTS: Crocin attenuated Aß25-35-induced spatial learning and memory deficiency and hippocampal neuron injury. Furthermore, the Western blot and qRT-PCR results showed that Crocin effectively suppressed inflammation and activated the PI3K/AKT pathway in Aß25-35-induced mice. CONCLUSION: Crocin restrained neuroinflammation via the activation of the PI3K/AKT pathway, thereby ameliorating the cognitive dysfunction of AD mice.

Curcumin alleviates Alzheimer's disease by inhibiting inflammatory response, oxidative stress and activating the AMPK pathway.

BACKGROUND: Alzheimer's disease (AD) is a common degenerative brain disorder with limited therapeutic options. Curcumin (Cur) exhibits neuroprotective function in many diseases. We aimed to explore the role and mechanism of Cur in AD. MATERIALS AND METHODS: Firstly, we established AD mice by injecting amyloid-ß1-42 (Aß1-42) solution into the hippocampus. Then, the AD mice received 150 mg/kg/d Cur for 10 consecutive days. The Morris water maze test was conducted to evaluate the cognitive function of the mice by hidden platform training and probe trials. To assess the spatial memory of the mice, spontaneous alternation behavior, the number of crossing the novel arm and the time spent in the novel arm during the Y-maze test was recorded. Hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNAL) assay were performed to assess the pathological damage and apoptosis of brain tissues. The number of damaged neurons was inspected by Nissl staining. Immunohistochemical staining was then performed to detect Aß1-42 deposition. The levels of tumor necrosis factor-α (TNF-a), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in serum and hippocampus, the contents of super oxide dismutase (SOD) and malondialdehyde (MDA) in brain tissues were assessed by enzyme-linked immunosorbent assay (ELISA). Additionally, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), RelA (p65) protein expressions and Adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation were tested using Western blot. RESULTS: Cur not only improved cognitive function and spatial memory, but also alleviated the pathological damage and apoptosis of brain tissues for AD mice. Meanwhile, upon Cur treatment, the number of damaged neurons in AD mice was decreased, the level of Aß1-42 in AD mice was significantly decreased. Furthermore, the AD mice treated with Cur exhibited lower TNF-a, IL-6, IL-1ß and MDA levels and a higher SOD content. Besides, Cur also downregulated p65 expression and upregulated AMPK phosphorylation. CONCLUSION: Cur may improve AD via suppressing the inflammatory response, oxidative stress and activating the AMPK pathway, suggesting that Cur may be a potential drug for AD.

Ginsenoside Rg2 alleviates neurovascular damage in 3xTg-AD mice with Alzheimer's disease through the MAPK-ERK pathway.

Alzheimer's disease (AD) is the most common form of dementia, and ginsenoside Rg2 (Rg2) is proven to inhibit AD's progression. This study investigates the potential benefits of Rg2 treatment on 3xTg-AD mice. Following 6 weeks of gavage treatment, Rg2-treated 3xTg-AD mice exhibited improved spatial recognition memory behaviors, regional cerebral blood flow, and histopathological injury of the hippocampus, which were observed through a Y-maze test, laser Doppler flowmetry, and hematoxylin-eosin staining. Additionally, Rg2 treatment caused a decrease in the levels of amyloid beta 25-35, TNF-α, IL-1ß, and IL-6, as measured by enzyme-linked immunosorbent assay, as well as a reduction in mRNA levels of IL-1ß and IL-6 in 3xTg-AD mouse brains using quantitative real-time PCR. In particular, NeuN and CD31 levels were inhibited and GFAP level was elevated in 3xTg-AD mice that were observed through immunofluorescence, and these levels were all antagonized by Rg2, suggesting the effects of Rg2 on neurovascular damage, astrocyte activation, and neuronal loss. Furthermore, Western blot and qRT-PCR assays showed that Rg2 blocked the expression of ICAM-1 and VCAM-1 in 3xTg-AD mice. By Western blot, the ratios of p-ERK/ERK and p-MAPK/MAPK in 3xTg-AD mice were upregulated by Rg2 treatment, suggesting the neuroprotective effects of Rg2 may be related to the MAPK-ERK pathway. In summary, this study demonstrated the potential of Rg2 to improve AD and provided a scientific basis for research on the biological mechanism of AD and the development of Rg2.

[Correlation of behavioral performance with expressions of substance P and neurokinin-1 receptor in the L5－S2 spinal cord of chronic prostatitis rats].

OBJECTIVE: To investigate the correlation between the behavioral performance and the expressions of substance P (SP) and neurokinin-1 receptor (NK-1R) in the posterior horn of the L5－S2 spinal cord in rats with chronic prostatitis (CP). METHODS: A CP model was made in 30 adult male SD rats by intraperitoneal injection of 0.5 ml dyphtheria pertussis tetanus (DPT) vaccine and mixed solution of 1 ml prostatein extract and complete adjuvant in a 1∶1 ratio, and another 10 rats were injected with the same volume of normal saline as controls. At 45 (n = 10), 60 (n = 10) and 90 days (n = 10) after modeling, the behavioral changes of the rats were observed by open-field and sucrose consumption tests, the prostatic indexes and levels of serum TNF-α, IL-1ß, IL-2 and IL-10 were obtained, and the expressions of SP and NK1-R in the L5－S2 spinal cord were determined by immunohistochemistry. RESULTS: Compared with the controls, the CP model rats showed obviously decreased horizontal and vertical movement scores and sucrose consumption, particularly in the 90 d group (P < 0.05), significantly reduced prostatic indexes in the 45 d, 60 d and 90 d groups (all P < 0.05), even lower in the 90 d than in the 45 d and 60 d groups (P < 0.05). Edema and lymphocytes were increased in the prostatic tissue with the prolonged time of modeling. The levels of serum TNF-α, IL-1ß, IL-2 and IL-10 were markedly elevated in all the CP rats as compared with those in the controls (P < 0.05), and so were the expressions of SP and NK-1R in the L5－S2 spinal cord (P < 0.05), even more significantly in the 90 d than in the 45 d and 60 d groups (P < 0.05). CONCLUSIONS: Rats with chronic prostatitis are characterized by behavioral manifestation of depression, increased levels of serum TNF-α, IL-1ß, IL-2 and IL-10, and a time-dependent upregulation of the expressions of SP and NK-1R in the posterior horn of the L5-S2 spinal cord, which suggests a correlation between the behavioral performance and the expressions of SP and NK-1R in the L5－S2 spinal cord of the rats.

Atorvastatin Attenuates Ischemia/Reperfusion-Induced Hippocampal Neurons Injury Via Akt-nNOS-JNK Signaling Pathway.

Ischemia-induced brain damage leads to apoptosis like delayed neuronal death in selectively vulnerable regions, which could further result in irreversible damages. Previous studies have demonstrated that neurons in the CA1 area of hippocampus are particularly sensitive to ischemic damage. Atorvastatin (ATV) has been reported to attenuate cognitive deficits after stroke, but precise mechanism for neuroprotection remains unknown. Therefore, the aims of this study were to investigate the neuroprotective mechanisms of ATV against ischemic brain injury induced by cerebral ischemia reperfusion. In this study, four-vessel occlusion model was established in rats with cerebral ischemia. Rats were divided into five groups: sham group, I/R group, I/R+ATV group, I/R+ATV+LY, and I/R+SP600125 group. Cresyl violet staining was carried out to examine the neuronal death of hippocampal CA1 region. Immunoblotting was used to detect the expression of the related proteins. Results showed that ATV significantly protected hippocampal CA1 pyramidal neurons against cerebral I/R. ATV could increase the phosphorylation of protein kinase B (Akt1) and nNOS, diminished the phosphorylation of JNK3 and c-Jun, and further inhibited the activation of caspase-3. Whereas, all of the aforementioned effects of ATV were reversed by LY294002 (an inhibitor of Akt1). Furthermore, pretreatment with SP600125 (an inhibitor of JNK) diminished the phosphorylation of JNK3 and c-Jun, and further inhibited the activation of caspase-3 after cerebral I/R. Taken together, our results implied that Akt-mediated phosphorylation of nNOS is involved in the neuroprotection of ATV against ischemic brain injury via suppressing JNK3 signaling pathway that provide a new experimental foundation for stroke therapy.

Shrinking the malaria map in China: measuring the progress of the National Malaria Elimination Programme.

BACKGROUND: Remarkable progress has been made towards the elimination of malaria in China since the National Malaria Elimination Programme (NMEP) was launched in 2010. The incidence of locally-acquired malaria cases has declined rapidly and endemic areas have also dramatically shrunk. In total, 3 078 malaria cases were reported in 2014, but only 56 cases were indigenous. In order to further promote the elimination programme, we reviewed the progress of and experiences associated with malaria elimination in China, and identified the challenges and priorities for the next stage of the programme. METHODS: Data were collected from the web-based China Information System for Disease Control and Prevention, and the China Annual Report of Malaria Elimination. The progress towards the elimination of malaria from 2010 to 2014 was measured. RESULTS: During the implementation of the NMEP from 2010 to 2014, local malaria incidence has declined continuously, only remaining in the Yunnan Province and Tibet Autonomous Region in 2014. By the end of 2015, 75.6 % (1 636/2 163) of the malaria-endemic counties passed the sub-national elimination assessment. The main challenges are cases of border malaria and imported malaria from other countries. Sustainable support and investment from the government, the establishment of an effective surveillance and response system, and risk assessments for the potential reintroduction of malaria are priorities for the next stage of the elimination programme. CONCLUSIONS: The NMEP in China has been successfully implemented thus far and the malaria map has shrunk dramatically. The priorities for malaria elimination are interventions to block transmission at border areas, management of imported malaria cases, preventing malaria reintroduction, capacity building, and sustainability of malaria surveillance and response.

Long-Term Follow-Up of a Community Assignment, One-Time Endoscopic Screening Study of Esophageal Cancer in China.

PURPOSE: There are no global screening recommendations for esophageal squamous cell carcinoma (ESCC). Endoscopic screening has been investigated in areas of high incidence in China since the 1970s. This study aimed to evaluate whether an endoscopic screening and intervention program could reduce mortality caused by ESCC. METHODS: Residents age 40 to 69 years were recruited from communities with high rates of ESCC. Fourteen villages were selected as the intervention communities. Ten villages not geographically adjacent to intervention villages were selected for comparison. Participants in the intervention group were screened once by endoscopy with Lugol's iodine staining, and those with dysplasia or occult cancer were treated. All intervention participants and a sample consisting of one tenth of the control group completed questionnaires. We compared cumulative ESCC incidence and mortality between the two groups. RESULTS: Three thousand three hundred nineteen volunteers (48.62%) from an eligible population of 6,827 were screened in the intervention group. Seven hundred ninety-seven volunteers from an eligible population of 6,200 in the control group were interviewed. Six hundred fifty-two incident and 542 fatal ESCCs were identified during the 10-year follow-up. A reduction in cumulative mortality in the intervention group versus the control group was apparent (3.35% v 5.05%, respectively; P < .001). Furthermore, the intervention group had a significantly lower cumulative incidence of ESCC versus the control group (4.17% v 5.92%, respectively; P < .001). CONCLUSION: We showed that endoscopic screening and intervention significantly reduced mortality caused by esophageal cancer. Detection and treatment of preneoplastic lesions also led to a reduction in the incidence of this highly fatal cancer.

[Impact of hip fracture on coagulation function in elderly patients].

OBJECTIVE: To investigate the impact of hip fracture on coagulation function in elderly patients. METHODS: In our study, 127 elderly patients with hip fracture were diagnosed and admitted to Peking University People's Hospital from January 2011 to March 2012. Specimens of their venous blood were obtained before and after the surgery, and measured for fibrinogen (FIB) and D-dimer. Also, we analyzed their age, type of fracture, fracture time, and concomitant diseases. RESULTS: The FIB level of the patients (127 cases) before surgery was (3.91 ± 1.06) g/L, and 42.52% (54/127) patients' FIB was higher than normal. After the surgery, 28 patients underwent FIB test [(4.21 ± 1.24) g/L], which was higher than the FIB value before surgery, but was not statistically significant. Before surgery, 15 patients underwent D-dimer test [(2 059.5 ± 1 948.0) µg/L]. After the surgery, 26 patients underwent D-dimer test [(2 574.9 ± 1 702.4) µg/L].The two values were significantly higher than normal (P<0.05). The elevated value of FIB had no relationship with age, diabetes, cardiovascular or cerebrovascular diseases. Before surgery, 45.83% (22/48) of the intertrochanteric fracture patients had abnormal FIB, and 40.50% (32/79) of the patients with femoral neck fracture had abnormal FIB, but they were not statistically significant. Grouped according to the fracture time, when fracture time was longer than 96 h, the ratio of abnormal FIB was 26.7%, lower than those of other groups, and the difference was statistically significant (P<0.05). CONCLUSION: The hip fracture in elderly patients has a direct impact on coagulation system, and FIB and D-dimer have significantly changed. According to the variation of FIB after fracture,we speculate that fracture surgery after 96 h may affect the coagulation system at the lowest level.

Environmental exposure and p53 mutations in esophageal cancer patients in areas of low and high incidence of esophageal cancer in China.

Esophageal cancer is the 6th most common cancer in the world, and genetic factors (p53 mutations) in addition to the environmental factors (food, nutrition, smoking, drinking, etc.) are involved in its development. In this study, the association between the both factors, environmental risk factors for esophageal cancer and p53 mutations, in tumor tissues was investigated in 77 patients living in a high-incidence area and 50 patients living in a low-incidence area in Hebei Province, China. Among these patients, p53 mutations were observed in about 50%, without regional differences in the respective frequencies. G:C>A:T (G to A or C to T) transition mutations were the major type of mutations observed in patients in the high-incidence area (19 patients, 50%), whereas G:C>A:T transitions and insertions were observed with equal frequency (8 patients, 33.3%) in the low-incidence area. As for the association with environmental factors, p53 mutations occurred with higher frequency in patients with a daily intake of spicy foods and in those who used unboiled well water in the low-incidence area. Logistic regression analysis showed no association between food intakes and p53 mutations in high- and low-incidence areas. Thus, higher frequency of spicy food intake and use of unboiled well water may be risk factors of esophageal cancer via p53 mutations in China.

Age scope of high-risk population for esophageal cancer in Ci county.

AIM: To define the age scope of high-risk population for esophageal cancer (EC) in Ci county. METHODS: The results of endoscopic examination of 2 013 subjects, cytological screening of 16 763 persons and records of 9 265 patients with EC were analyzed by Ridit methods, the standard age group was 45-49 year group. RESULTS: The average age of patients with moderate esophageal epithelium dysplasia by endoscopic examination was 53.5 years, of severe esophageal epithelium dysplasia, 51.4 years, early EC, 55.6 years. The average age of stage one severe epithelium dysplasia (SEEDI) by cytological screening was 51.2 years, of stage two severe epithelium esophageal dysplasia (SEED II) 51.6 years, of advanced EC 61.7 years. In the group of 40-year olds, the value of Ridit by pathological diagnosis was 0.46, 95% CI, 0.45-0.47, that by cytological diagnosis was 0.45, 95% CI, 0.43-0.47. As the age increased at five-year intervals, the value of Ridit increased significantly. CONCLUSION: In Ci county of a high incidence area of EC, the age definition of high-risk population should be above 45 years.

DHPLC is superior to SSCP in screening p53 mutations in esophageal cancer tissues.

Mutations of the p53 tumor-suppressor gene universally occur on exons 5-8 in human cancer. We analyzed these mutations in esophageal cancer tissue from 207 patients in China using 2 methods, single-strand conformation polymorphism (SSCP), one of the most frequently used methods, and the recently developed denaturing high-performance liquid chromatography (DHPLC), and compared their sensitivity and efficiency. Exons 5-8 of p53 were amplified from esophageal cancer tissue genomes, screened for fragments of mutations and polymorphisms by SSCP and DHPLC in a blind study and confirmed by direct sequencing to detect the mutations and polymorphisms. The numbers detected by DHPLC were greater than those detected by SSCP, though the rate of mutations and polymorphisms was lower in SSCP than in DHPLC, which appeared to detect smaller mutations (substitutions and 1 bp insertions/deletions). Of the mutations with substitutions detected by DHPLC but not by SSCP, 50% substituted adenosine for other nucleotides, suggesting that these mutations are often missed when SSCP is used. According to these data, the sensitivity of SSCP and DHPLC was 81% and 97%, respectively, and the specificity was 97% and 85%, respectively. Our results suggest that DHPLC may be recommended over SSCP when screening gene mutations. Thus, rates of p53 mutations and polymorphisms in esophageal cancer tissue in Chinese patients were 49% and 41% by DHPLC and SSCP, respectively.

Endoscopic survey of esophageal cancer in a high-risk area of China.

AIM: To characterize the histological types of esophageal and cardiac mucosa by endoscopic survey of a population in a high-risk area of esophageal cancer of China. METHODS: A selected cohort of residents in Cixian County during December 2001 and May 2002 was surveyed by using Lugol's staining, followed by computer-based statistical analysis of the data with SPSS 10.0 software. RESULTS: Histologically, the detection rates of squamous epithelial acanthosis, squamous epithelial atrophy, and basal cell hyperplasia in the esophagus were 1.9% (38/2,013), 0.1% (3/2,013) and 0.9% (18/2,013) respectively, and those of mild, moderate, and severe esophagitis were 34.9% (703/2,013), 1.6% (33/2,013) and 0.2% (2/2,013) respectively. Mild, moderate, and severe esophageal dysplasia were detected in 8.6% (172/2,013), 7.8% (157/2,013) and 2.6% (53/2,013) respectively in the selected population, whereas in situ carcinoma, intramucosal carcinoma, invasive squamous carcinoma of the esophagus in 2.5% (50/2,013), 0.2% (4/2,013) and 0.7% (14/2,013) respectively. The detection rates of non-atrophic gastritis and atrophic gastritis of the cardia were 36.3% (730/2,013) and 11.5% (232/2,013) respectively, with mild and severe dysplasia of the cardia detected in 2.5% (51/2,013) and 0.8% (17/2,013), respectively, in this population; the rates of intramucosal adenocarcinoma and invasive adenocarcinoma of the cardia were 0.1% (3/2,013) and 0.8% (17/2,013) respectively. The detection rate of esophageal cancer at early stage was 79.4% (54/68). The survey rate (ratio of examined population to expected population) was 73.8% (2,013/2,725). CONCLUSION: Histologic types of the esophageal and cardiac mucosa were characterized by endoscopic survey in a high-risk population of esophageal cancer, which may help the early detection and treatment of esophageal and cardiac cancers and dysplasia, and reduce the mortality of such malignancies.

An analysis of esophageal cancer incidence in Cixian county from 1974 to 1996.

AIM: To describe the incidence of esophageal cancer (EC) in Cixian, a county of Hebei province during 1974-1996. We analyzed the sex and age characteristics as well as the geographic distribution of EC, in order to determine the impact so that methods of preventing and controlling EC in Cixian can be put in place. METHODS: Since the early 1970s, the cancer registry system has been established, which collects the cancer incidence in Cixian county. The malignant tumors were coded according to International Classification of Disease IX (ICD-9). All the data were checked and analyzed using EPIINFO. RESULTS: The trend of the incidence rate of EC from 1974 to 1996 had declined, (229.9/100 000 vs 178.5/100 000, Odds ratio=1.47, 95 % CI:1.32-1.63, chi(2)=52.89. trend chi(2)=26.54, P<0.001). The incidence rate of males declined significantly (281.81/100 000 vs 157.96/100 000, Odds ratio=1.61, 95 % CI: 1.41-1.84, chi(2)=47.85. Trend chi(2)=44.86, P<0.001), whereas, the females remained steady (157.96/100 000 vs 133.41/100 000, odds ratio=1.28, 95 % CI:1.17-1.49, chi(2)=9.26. trend chi(2)=2.69, P>0.05). Male average annual incidence rate was 142.80/100 000 and the female's was 95.18/100 000. The sex ratio (males to females) was 1.50:1. The incidence rate was increasing along with the age. As to the geographic distribution, the incidence rate in mountainous areas and hilly areas showed a significantly declining trend (mountainous areas, trend chi(2)=149.93, P<0.001; hilly areas, trend chi(2)=42.70, P<0.001). The incidence rate of EC in plain areas had increased (trend chi(2)=22.39, P<0.001). CONCLUSION: The incidence rate of EC in Cixian county shows a trend and has declined after two decades, especially in mountainous area. But compared to other regions in the world, Cixian county still had a high incidence rate of EC.